Pyridinyl Amides for the Treatment of CNS and Metabolic Disorders

• US 20090197859A1
• Filed: 02/04/2009
• Published: 08/06/2009
• Est. Priority Date: 02/05/2008
• Status: Abandoned Application

• Current Assignee: Pfizer Inc.
• Original Assignee: Pfizer Inc.
• Inventors: Collantes, Elizabeth Martha, Schwarz, Jacob Bradley
• Application Number:
  US12/365,305
• Publication Number:
  US 20090197859A1
• Time in Patent Office: Days
• US Class Current: 514/210.2
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: C07D 213/81 Amides; Imides
• CPC Class Codes: C07D 401/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: G11C 13/0004 comprising amorphous/crystalline phase transition cells
• CPC Class Codes: G11C 13/0023 Address circuits or decoders
• CPC Class Codes: G11C 13/003 Cell access
• CPC Class Codes: G11C 2213/72 Array wherein the access device being a diode
• CPC Class Codes: G11C 2213/74 Array wherein each memory cell has more than one access device
• CPC Class Codes: G11C 2213/78 Array wherein the memory cells of a group share an access device, all the memory cells of the group having a common electrode and the access device being not part of a word line or a bit line driver
• CPC Class Codes: G11C 2213/79 Array wherein the access device being a transistor
• CPC Class Codes: G11C 5/025 Geometric lay-out considerations of storage- and peripheral-blocks in a semiconductor storage device geometrical lay-out of the components in integrated circuits, H01L27/0207
• CPC Class Codes: G11C 5/063 Voltage and signal distribution in integrated semi-conductor memory access lines, e.g. word-line, bit-line, cross-over resistance, propagation delay

Abstract

The present invention relates to novel pyridinyl derivatives of Formula

• • wherein Y, Z, L, R¹ through R¹¹, n, m, p, q, t are as defined herein, that are 5-HT receptor ligands, particularly the 5-HT6 subtype, and as such are useful for treating diseases wherein modulation of 5-HT activity is desired. The present invention relates to novel pyridinyl derivatives including their pharmaceutically acceptable salts. The invention also relates to processes for the preparation of, intermediates used in the preparation of, pharmaceutical compositions containing and the uses of such compounds in treating diseases of the central nervous system such as schizophrenia.

Claims

1. A compound formula

2. A compound according to claim 1 wherein, Y is —

C(R⁷)— and

the dashed line (- - -) is absent, or a pharmaceutically acceptable salt thereof.

3. A compound according to claim 2 wherein, Y is —

C(R⁷)— and

R⁷ is hydrogen or a pharmaceutically acceptable salt thereof.

4. A compound according to claim 2 wherein, Y is —

C(R⁷)— and

R⁷ is halo or a pharmaceutically acceptable salt thereof.

5. A compound according to claim 1 wherein, Y is >

N— and

the dashed line (- - -) is absent, or a pharmaceutically acceptable salt thereof.

6. A compound according to claim 5 wherein, m is zero, or a pharmaceutically acceptable salt thereof.

7. A compound according to claim 5 wherein, m is one, or a pharmaceutically acceptable salt thereof.

8. A compound according to claim 6 wherein, R³ is hydrogen, or a pharmaceutically acceptable salt thereof.

9. A compound according to claim 6 wherein, R³ is (C₁-C₆)alkyl optionally substituted with by one, two or three substituents independently selected from hydrogen, halo, —

CF₃, —

OCF₃, hydroxyl, amino, (C₁-C₆)alkylamino-, di((C₁-C₆)alkyl)amino-, (C₁-C₆)alkyl-, (C₁-C₆)alkoxy-, (C₃-C₁₀)cycloalkyl-, (C₁-C₉)heterocycloalkyl-, (C₆-C₁₀)aryl-, and —

(C₁-C₉)heteroaryl-, or a pharmaceutically acceptable salt thereof.

10. A compound according to claim 9 wherein said R³ (C₁-C₆)alkyl is methyl optionally substituted with by one, two or three substituents independently selected from hydrogen, halo, —

CF₃, —

OCF₃, hydroxyl, amino, (C₁-C₆)alkylamino-, di((C₁-C₆)alkyl)amino-, (C₁-C₆)alkyl- and (C₁-C₆)alkoxy-, or a pharmaceutically acceptable salt thereof.

11. A compound according to claim 5 wherein L is >

C═

O, or a pharmaceutically acceptable salt thereof.

12. A compound according to claim 5 wherein L is —

SO₂—

, or a pharmaceutically acceptable salt thereof.

13. A compound according to claim 5 wherein q is 1 or 2 and each R⁶ is independently selected from the radicals consisting of halo, —

CF₃, —

CN, —

NO₂, —

(C═

O)R⁸, —

(C═

O)OR⁹, —

O(C═

O)R⁸, —

OCF₃, —

OR⁹, —

O(C═

O)OR⁹, —

NR¹⁰R¹⁰, —

(NR¹⁰)(C═

O)R⁸, —

SR¹¹, —

(S═

O)R¹¹, —

SO₂R¹¹, (C₁-C₆)alkyl-, (C₂-C₆)alkenyl-, (C₂-C₆)alkynyl-, (C₃-C₁₀)cycloalkyl-, (C₆-C₁₀)aryl-, and (C₁-C₉)heteroaryl-;

wherein each of the aforesaid radicals may be optionally substituted by one, two or three substituents independently selected from hydrogen, halo, —

CF₃, —

OCF₃, hydroxyl, amino, (C₁-C₆)alkylamino-, di((C₁-C₆)alkyl)amino-, (C₁-C₆)alkyl-, (C₁-C₆)alkoxy-, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl-, (C₃-C₁₀)cycloalkyl-, (C₅-C₁₀)cycloalkenyl-, (C₆-C₁₀)bicycloalkyl-, (C₆-C₁₀)bicycloalkenyl-, (C₁-C₉)heterocycloalkyl-, (C₂-C₉)heterocycloalkenyl-, (C₂-C₉)heterobicycloalkyl-, (C₂-C₉)heterobicycloalkenyl-, (C₅-C₁₀)aryl, and (C₁-C₉)heteroaryl-, or a pharmaceutically acceptable salt thereof.

14. A compound according to claim 5 wherein Z is a bond, or a pharmaceutically acceptable salt thereof.

15. A compound according to claim 5 wherein Z is —

O—

, or a pharmaceutically acceptable salt thereof.

16. A compound according to claim 5 wherein R¹ and one of said R² are taken together with the carbon or nitrogen to which they are attached to form an optionally substituted 3 to 10 membered heterocyclic ring optionally containing one or two double or triple bonds and optionally containing one or two additional heteroatoms selected from N, S and O, or a pharmaceutically acceptable salt thereof.

17. A compound according to claim 16 wherein said optionally substituted 3 to 10 membered heterocyclic ring optionally containing one or two double or triple bonds is selected from azetidinyl, pyrrolidinyl, 3-pyrolin-1-yl, piperidinyl, 1,2,3,6-tetrahydropyridin-1-yl, perhydroazepinyl, heptamethyleneinyl, octahydroazoninyl, azabicyclo(2.2.1)heptan-3-one, and tropanyl, or a pharmaceutically acceptable salt thereof.

18. A compound according to claim 5 wherein two of said R² groups are taken together with the carbon to which they are attached to form an optionally substituted 3 to 10 membered carbocyclic ring optionally containing one or two double or triple bonds;

and wherein said 3 to 10 membered carbocyclic ring may optionally contain 1, 2 or 3 additional heteroatoms, or a pharmaceutically acceptable salt thereof.

19. A compound according to claim 18 wherein said optionally substituted 3 to 10 membered carbocyclic or heterocyclic ring optionally containing one or two double or triple bonds is selected from cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadinenyl, azetidinyl, pyrolidinyl, and piperidinyl, or a pharmaceutically acceptable salt thereof.

20. A compound according to claim 1 wherein said compound is:

(6-Piperazin-1-yl)-pyridin-2-yl)-(4-o-tolyl-piperidin-1-yl)-methanone;

[4-(3-Fluoro-2-methyl-phenyl)-piperidin-1-yl]-[6-(4-methyl-piperazin-1-yl)-pyridin-2-yl]-methanone;

[4-(4-Fluoro-2-methyl-phenyl)-piperidin-1-yl]-[6-(4-methyl-piperazin-1-yl)-pyridin-2-yl]-methanone;

[4-(5-Fluoro-2-methyl-phenyl)-piperidin-1-yl]-[6-(4-methyl-piperazin-1-yl)-pyridin-2-yl]-methanone;

[4-(2-Fluoro-6-methyl-phenyl)-piperidin-1-yl]-[6-(4-methyl-piperazin-1-yl)-pyridin-2-yl]-methanone;

[4-(2-Fluoro-phenyl)-piperidin-1-yl]-[6-(4-methyl-piperazin-1-yl)-pyridin-2-yl]-methanone;

[4-(2,3-Difluoro-phenyl)-piperidin-1-yl]-[6-(4-methyl-piperazin-1-yl)-pyridin-2-yl]-methanone;

[4-(2,4-Difluoro-phenyl)-piperidin-1-yl]-[6-(4-methyl-piperazin-1-yl)-pyridin-2-yl]-methanone;

[4-(2,5-Difluoro-phenyl)-piperidin-1-yl]-[6-(4-methyl-piperazin-1-yl)-pyridin-2-yl]-methanone;

[4-(2,6-Difluoro-phenyl)-piperidin-1-yl]-[6-(4-methyl-piperazin-1-yl)-pyridin-2-yl]-methanone;

[4-Fluoro-4-(2-fluoro-phenyl)-piperidin-1-yl]-[6-(4-methyl-piperazin-1-yl)-pyridin-2-yl]-methanone;

(4-Fluoro-4-o-tolyl-piperidin-1-yl)-[6-(4-methyl-piperazin-1-yl)-pyridin-2-yl]-methanone;

6-(1-Methyl-pyrrolidin-3-yl)-pyridin-2-yl]-(4-o-tolyloxy-piperidin-1-yl)-methanone;

[4-(2-Fluoro-phenoxy)-piperidin-1-yl]-(6-pyrrolidin-3-yl-pyridin-2-yl)-methanone;

[4-(2-Chloro-phenoxy)-piperidin-1-yl]-[6-(1-methyl-pyrrolidin-3-yl)-pyridin-2-yl]-methanone;

or

[6-(1-Methyl-pyrrolidin-3-yl)-pyridin-2-yl]-[4-(2-trifluoromethyl-phenoxy)-piperidin-1-yl]-methanone;

or a pharmaceutically acceptable salt of each of the foregoing compounds.

21. A compound according to claim 1 wherein said compound is:

[4-(4-Fluoro-2-methyl-phenoxy)-piperidin-1-yl]-[6-(1-methyl-pyrrolidin-3-yl)-pyridin-2-yl]-methanone;

[4-(2,5-Difluoro-phenoxy)-piperidin-1-yl]-[6-(1-methyl-pyrrolidin-3-yl)-pyridin-2-yl]-methanone;

[4-(2,4-Difluoro-phenyl)-piperidin-1-yl]-[6-(1-methyl-pyrrolidin-3-yl)-pyridin-2-yl]-methanone;

[4-(4-Fluoro-2-methyl-phenyl)-piperidin-1-yl]-[6-(1-methyl-pyrrolidin-3-yl)-pyridin-2-yl]-methanone;

[4-(5-Fluoro-2-methyl-phenyl)-piperidin-1-yl]-[6-(1-methyl-pyrrolidin-3-yl)-pyridin-2-yl]-methanone;

[4-(2-Fluoro-6-methyl-phenyl)-piperidin-1-yl]-[6-(1-methyl-pyrrolidin-3-yl)-pyridin-2-yl]-methanone;

or

[4-(2-Fluoro-6-methyl-phenyl)-piperidin-1-yl]-[6-(3-fluoro-1-methyl-pyrrolidin-3-yl)-pyridin-2-yl]-methanone;

or a pharmaceutically acceptable salt of each of the foregoing compounds.

22. A method for treating schizophrenia in a mammal comprising administering to a mammal a therapeutically effective amount of a compound of Formula I according to claim 1, or a pharmaceutically acceptable salt thereof.

23. A pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I, according to claim 1, or a pharmaceutically acceptable salt thereof.